In order for the nervous system to develop and function normally, many processes must occur. Neurons must be spaced appropriately, they must send out axons and dendrites that extend through the tissue to develop arbors and find targets, and they must form synapses to communicate with partners. Defects at any of these points can lead to dysfunction and neurodevelopmental disorders. The Down syndrome cell adhesion molecule (Dscam) gene is on the region of chromosome 21 that is associated with trisomies in Down syndrome. In the mouse retina, Dscam and the very similar Dscam Like (DscamL1) are involved in adhesive masking, a cellular process important for self-avoidance, allowing cell spacing and dendrite arborization. The Dscams are also involved in some aspects of synapse development. There are a few proteins known to interact with the Dscams: Pak1 (p21-activated kinase) can be activated by Dscam, and the MAGI (membrane- associated guanylate kinase with inverted domain structure) family of scaffolding molecules interacts with the c-terminus of the Dscams. The aim of the experiments described in this proposal is to elucidate the signaling mechanisms downstream of the Dscams during adhesive masking and synapse development. The overall hypothesis is that Dscams regulate adhesive masking early in development through activation of Pak1, and are important for synapse maturation later in development through interactions with the MAGI proteins. To test this hypothesis, retina ganglion cells will be cultured in a system that allows the assessment of adhesive masking and the manipulation of gene expression. Experiments will also be performed in the mouse by making new mouse lines in which Dscam and DscamL1 have targeted mutations that do not allow the proteins to interact with the MAGIs. It is expected that the results will show that the Dscams carry out their different functions through distinct signaling mechanisms. These findings will have implications for the mechanisms of the Dscams'possible role in the pathology of Down syndrome and other neurodevelopmental disorders including congenital retinopathies. PUBLIC HEALTH RELEVANCE: The aim of this proposal is to study the molecular mechanisms by which the mouse ortholog of Down syndrome cell adhesion molecule (Dscam) and the similar Dscam Like (DscamL1) function in the cellular recognition events that direct retinal development. In humans, Dscam is in region of Chromosome 21 associated with Down syndrome trisomies, and understanding the basic molecular mechanisms of the Dscams'function will help to define its possible role in the phenotypes associated with Down syndrome and other neurodevelopmental disorders. Studying these mechanisms in the retina may provide insight into human congenital retinopathies as well.